New long-acting injectable microcapsule contraceptive system

Abstract

A new long-acting, injectable contraceptive which provides continuous controlled release of the steroid norethisterone (NET) for a precise period of 6 months following a single intramuscular injection is described. The prototype system consists of microcapsules made of the biodegradable polymer d, l-polylactic acid, in which micronized crystals of NET are homogeneously dispersed. NET is slowly released from the microcapsules following intramuscular injection at a rate of 0.90 microgram NET/day/mg of microcapsule by diffusion of the steroid from the polymer matrix. Three different doses of a standard preparation of microcapsules were tested in normally cycling female babbons (4 to 5 baboons/group). Following injection of either 300, 200, or 100 mg of microcapsules containing 75, 50, or 25 mg of NET, blood samples were collected at selected intervals and analyzed for NET, estrogen, and progesterone by radioimmunoassay. All three doses provided continuous NET release for 6 months following injection. The NET serum profiles for the different doses are parallel, and ovulation was inhibited in all baboons for 6 months following treatment.

PIP: A new, long-acting, injectable contraceptive system which uses a biodegradable polymer (d,1-polylactic acid) in the form of microspheres for controlled delivery of norethisterone is described. The continuous controlled release is designed to last exactly 6 months after a single intramuscular injection. System fabrication has yielded a prototype: Microcapsules of the biodegradable polymer containing homogeneously dispersed micronized crystals of norethisterone are injected, and the steroid is released slowly at a rate of .9 mcg of norethisterone/day/mg of microcapsule by diffusion of the drug through the polymer matrix. Pharmacokinetics of the injectable system of norethisterone were tested in normally cycling female baboons. 3 different doses of a standard preparation were tested (4-5 animals/group). After injection of either 300, 200, or 100 mg of microcapsules of 75, 50, or 25 mg of norethisterone, blood samples were collected and analyzed for the steriod, estrogen, and progesterone; radioimmunoassay of samples collected at selected intervals was carried out. For 6 months after injection, all 3 doses were parallel. Ovulation was inhibited in all baboons for 6 months after treatment; each animal resumed normal ovarian function within 1-2 weeks after the norethisterone blood level fell below the level of detection of the assay system (10-25 pg/ml).